what drives persistent immune activation/inflammation in cart-treated hiv-1? giulia marchetti, md,...
TRANSCRIPT
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What drives persistent immune activation/inflammation in cART-treated HIV-1?
Giulia Marchetti, MD, PhD
Dept of Health Sciences, Clinic of Infectious Diseases - University of Milan, San Paolo Hospital, Italy
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The revolution of cART
Hammer, S et al. NEJM 1997; Palella, F et al. NEJM 1998
CD4+ HIV-RNA
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Full restoration of health upon cART?
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Samji et al. ART-Cohort Collaboration. PlosOne 2013
Life expectancy in cART-treated patientsART-Cohort Collaboration
22.937 individuals (82,022 person-year)
At age 20
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Serious non-AIDS events during long-term virologically suppressive cART
Tenorio et al. JID 2014
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HIV as an inflammatory disease
• Acute HIV associated with rapid/intense release of pro-inflammatory cytokines (IL-6, IP-10, TNF-a) and dramatic increase of activated innate immune cells T-, B-cells
• Chronic HIV: T-cell activation steady state
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High proportion of activated CD8+ T-cells in HIV
Giorgi, J et al. J Immunol 1993
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CD8 T-cell activation predicts CD4+ T-cell count over time
Deeks et al. Blood 2004
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Shorter survival is associated with T-lymphocyte activation
Giorgi, J et al. JID 1999
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In untreated infection T-cell activation is associated to HIV viral replication
Deeks S Blood 2004
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What happens upon cART?
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CD8+ T cell activation fails to fully normalize during effective cART
Hunt PW, et al. J Infect Dis. 2003;187:1534-1543.
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Chronic inflammation is a much more important determinant of mortality
in treated HIV
Kuller L PLOS Medicine 2008; also Hunt et al. AIDS 2011; Lok et al, AIDS 2013; Hunt et al. JID 2014; Tenorio et al JID 2014; …..
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What drives persistent immune
activation/inflammation in cART-treated
disease?
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What drives persistent immune activation/inflammation in cART-treated disease?
• Gut epithelial barrier dysfunction, microbiome and microbial translocation
• Co-infections (CMV et al….)• Residual HIV replication• Thymic dysfunction and residual defects in adaptive
immune responses• Lack of immunoregulatory responses- Lymphoid fibrosis• Co-morbid conditions (metabolic syndrome, central
adiposity)
![Page 16: What drives persistent immune activation/inflammation in cART-treated HIV-1? Giulia Marchetti, MD, PhD Dept of Health Sciences, Clinic of Infectious Diseases](https://reader030.vdocuments.mx/reader030/viewer/2022013004/56649f305503460f94c4b73f/html5/thumbnails/16.jpg)
What drives persistent immune activation/inflammation in cART-treated disease?
• Gut epithelial barrier dysfunction, microbiome and microbial translocation
• Co-infections (CMV et al….)• Residual HIV replication• Thymic dysfunction and residual defects in adaptive
immune responses• Lack of immunoregulatory responses- Lymphoid fibrosis• Co-morbid conditions (metabolic syndrome, central
adiposity)
![Page 17: What drives persistent immune activation/inflammation in cART-treated HIV-1? Giulia Marchetti, MD, PhD Dept of Health Sciences, Clinic of Infectious Diseases](https://reader030.vdocuments.mx/reader030/viewer/2022013004/56649f305503460f94c4b73f/html5/thumbnails/17.jpg)
Gut epithelial barrier dysfunction,
microbiome and microbial translocation
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The GI tract as a site of HIV pathogenesis
Sandler & Douek, Nat Reviews 2012
Brenchley et al. Nat Med 2006
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Persistent Depletion of CD4+ T cells in the GI Tract despite Normalization in the Peripheral Blood
Mehandru S, Plos Med 2006
54 HIV+ patients (acute)
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Persistent damage to the gut tight epithelial barrier despite cART
HIV negative HIV+ cART-treated
Tincati C et al. CROI 2014
Chung; Plos. Path. 2014; (see also Somsouk AIDS 2015)
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Altered gut tight junctions associate with microbial translocation
0
100
200
300
HIVNegative
HAARTVL < 75
Untreated
P = 0.002
P = 0.001
Pla
sm
a L
PS
(p
g/m
L)
Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009
Chung et al. Plos. Path. 2014; (see also Somsouk AIDS 2015)
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(Altered) gut tight epithelial barrier as
driver of inflammation?
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Altered gut tight junctions associate with immune activation
Chung et al Plos. Path. 2014; (see also Somsouk AIDS 2015)
Tincati C et al. CROI 2014
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Altered gut microbioma in SIV/HIV
Brenchley Nat Med 2006; in humans: Gori et al. JCM 2008
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Only partial recovery of gut microbioma upon successful cART
50 HIV+ patients before (T0) and after 12 months
cART (T12)
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(Altered) intestinal microbioma as driver of
inflammation?
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Greater representation of proinflammatory/inflammation-thriving class-level bacteria
Correlation between gut microbioma and systemic immune activation
Ellis et al. JAIDS 2011, also Dillon et al. Mucosal Immunol 2014
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Persistent microbial translocation during cART
0
100
200
300
HIVNegative
HAARTVL < 75
Untreated
P = 0.002
P = 0.001P
las
ma
LP
S (
pg
/mL
)
Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009
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Microbial translocation hampers CD4+ T-cell recovery upon cART
Marchetti G et al. AIDS 2008; Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009
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Microbial translocation and immune activation: what is the cause what
is the effect?
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Microbial translocation causes immune activation: colocalization of E.coli and IFN-a in colon
Estes J et al. PLoS Pathogens 2010
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Microbial translocation is associated to immune activation
Brenchley J et al. Nat Med 2006
Marchetti G et al. AIDS 2008; Jiang et al. J Infect Dis 2009
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Exogenous LPS administration enhances immune activation and HIV replication
Pandrea et al J Immunol 2008; Pandrea et al. Blood 2012
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Bacterial products drive monocyte expression of thrombosplastin
Funderburg N et al Blood 2010
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In vitro LPS stimulation of monocyte-derived macrophages: cytokine/chemokine expression of genes involved in the TLR pathway
Merlini E et al ICI, International Congress of Immunology 2013
35 HIV+ cART-treated
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Stimulation of peripheral blood cells by TLR ligands increases expression of CD38 on CD4+ and CD8+ T-lymphocytes - HIV-negative
Funderburg N et al. PLoS One 2008
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In vitro LPS stimulation on PBMC: CD4 and CD8 T-cell activation, proliferation and apoptosis
Merlini E et al ICI, International Congress of Immunology 2013
35 HIV+ cART-treated
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Sevelamer treatment reduces MT during early SIVsab infection of PTMs
LNs stained for LPS core antigen (brown)
Kristoff J, JCI, 2014: 124 (6)
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Sevelamer treatment reduces immune activation/inflammation during early SIV infection in PTMs
Kristoff J, J Clin Invest 2014
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Sevelamer does not reduce LPS and sCD14 in chronic early-stage untreated HIV
Sandler N, J Infect Dis 2014
Should we test sevelamer in cART-
treated HIV?
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Altered balance of gut immunoregulatory cells
(e.g. Th17/Th22, gut-homing T-cells) as
driver of inflammation?
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Only partial recovery of gut-homing T-cells upon cART
20 HIV+ before and at 12 months cART
20 HIV+ cART-treated
Mavigner et al. JCI 2012
Basilissi M ICAR 2015
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Only partial recovery of gut-homing and Th17/Th22 T-cells upon cART
20 HIV+ before and at 12 months cART
Basilissi M ICAR 2015
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Low Th17/Treg ratio despite cART
Favre et al Science Transl Med 2010
20 HIV+ cART-treated
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Low Th17/Treg ratio is associated to immune activation
Favre et al Science Transl Med 2010
20 HIV+ cART-treated
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What drives persistent immune activation/inflammation in cART-treated disease?
• Gut epithelial barrier dysfunction, microbiome and microbial translocation
• Co-infections (CMV et al….)• Residual HIV replication• Thymic dysfunction and residual defects in adaptive
immune responses• Lack of immunoregulatory responses- Lymphoid fibrosis• Co-morbid conditions (metabolic syndrome, central
adiposity)
![Page 47: What drives persistent immune activation/inflammation in cART-treated HIV-1? Giulia Marchetti, MD, PhD Dept of Health Sciences, Clinic of Infectious Diseases](https://reader030.vdocuments.mx/reader030/viewer/2022013004/56649f305503460f94c4b73f/html5/thumbnails/47.jpg)
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Higher non-AIDS morbidity/mortality in HIV+/CMV-Ab+ patients
6111 HIV+ (5119 CMV-Ab+), 12% cART-treated
Lichtner M et al. J Infect Dis 2015
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Naeger D et al. PlosOne 2010
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cART-treated asymptomatic CMV seminal shedders present higher T-cell activation/proliferation
Gianella S et al. J Virol 2015
53 HIV+ cART-treated
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cART-treated asymptomatic CMV seminal shedders present higher T-cell expression of PD-1
45 HIV+ cART-treated
Dan J et al. CROI 2015
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Vita S et al. CROI 2015
Higher innate immunity markers in HIV/CMV co-infected patients on cART
69 HIV+ cART-treated
(46/69 CMV Ab+)
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Reduction of CD8 T-cell activation by valganciclovir……
Hunt et al., JID, 2011
30 HIV+, 70% cART-treated
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……but not valacyclovir
Yi TJ et al., CID, 2013
40 HIV+/HSV2+ cART-treated
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HCV coinfection was associated with increased risk of developing an ADI
(adjusted relative rate [ARR], 2.61; 95% confidence interval
[CI], 1.88–3.61)
*ARR, 3.15
*ARR, 3.87
*ARR, 2.68
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127 HIV-infected hepatitis viruses co-infected patients (118 HCV, 9 HBV)- ART naïve, CD4 cell count >200/μl- known date of prior HIV neg/pos tests
→immune activation (IA): IL-6,TNFα→microbial translocation (MT): LPS, sCD14
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Gonzalez et al et al. J Virol 2009
34 : 14 HCV+/HIV+
cART-treated; 11 HCV+; 9
HIV+ treated
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Hampered T-cell dynamics in HIV/HCV co-infected patients 356 HIV+ cART-
treated : 130 HCV co-infected
Zaegel-Fauchel O et al. AIDS 2015
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Hunt et al. JID 2003; also Greub G Lancet 2000
HCV co-infection is associated to higher T-lymphocyte activation on cART
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HCV treatment reduces immune activation ?
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Reduction of T-cell activation by anti-HCV treatment
Gonzalez et al et al. J Virol 2009; also Massanella M et al. Antiviral Therapy 2010
356 HIV+ cART-treated : 130 HCV co-
infected
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What drives persistent immune activation/inflammation in cART-treated disease?
• Gut epithelial barrier dysfunction, microbiome and microbial translocation
• Co-infections (CMV et al….)• Residual HIV replication• Thymic dysfunction and residual defects in adaptive
immune responses• Lack of immunoregulatory responses- Lymphoid fibrosis• Co-morbid conditions (metabolic syndrome, central
adiposity)
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Adapted from Deeks S – International Congress on Drug Therapy in HIV Infection, Glasgow UK 2-6 Nov 2014
Despite cART, HIV viremia persists indefinitely at very low level
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Immune activation does not correlate with residual plasma viremia…… Case: 123 HIV+
cART-treated with transient low level viremia (>50 <400 cp/ml)
Control: HIV+ cART-treated RNA<50cp/ml
Taiwo B et al. JAIDS 2013; also Chun TW et al. JID 2011 (including C-reactive protein, D-dimer, IL-6, soluble TNF receptor I); Steel A et al. Antiviral Therapy 2007…..
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Steel A et al. Antiviral Therapy 200.
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…but may associate with residual plasma viremia in the setting of poor immune recovery on cART….
Mauvigner M et al. PlosOne 2009
Marchetti G et al. AIDS 2006
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….Immune activation (and senescence) does associate with cell-associated HIV-DNA/RNA in peripheral blood ….
190 HIV+ cART-treated
Hatano H et al. JID 2012; also Stone SF HIV Med 2005
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….and in tissues
23 HIV+ cART-treated
Sheth PM et al. Mucosal Immuno 2008; also Yukl SA JID 2010; d’Ettorre G et al. Curr HIV Res 2011
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Hypothesis: if residual HIV replication sustains immune activation upon
cART, then cART intensification should
lower immune activation
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Any benefit by maraviroc intensification?
Wilkin et al., JID 2012
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Any benefit by maraviroc intensification?
Hunt et al., Blood, 2013
Rusconi et al., PLOSOne, 2013
97 HIV+ cART-treated with low
CD4+ immune recovery
45 HIV+ cART-treated with low CD4+ immune recovery
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Any benefit by integrase inhibitors intensification?30 HIV+ cART-treated with
low CD4+ immune recovery
Hatano H et al., JID, 2011; also Hatano H et al JAIDS 2012
Peripheral blood Gut
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Raltegravir induced a specific reduction of CD38 expression in CD8 T cells
Massanella et al., AIDS, 2012; also Vallejo A et al. AIDS 2012
Buzon MJ et al. Nat Med 2010;
69 HIV+ cART-treated
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Any differences in the effect on immune
activation by diverse cART class?
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CD4 231/uL; n=76AZT+ddI or AZT+3TC+ABC or EFV or IDV/r
Rizzardini et al., HIV Clin Trials 2006
Advanz StudyCD4<100/uL; n=65
AZT+3TC+EFV or LPV/r
Mirò et al. AIDS Res and Human Retrov 2010
Advanz 3 StudyCD4<100/uL; n=89
TDF+FTC+ EFV or ATZ/r or LPV/r
Mirò et al. JAIDS, 2015
Immuno StudyCD4<50>250/uL; n=35
TDF+FTC+ EFV or DRV 800mg/r
Tincati et al. under reviewData are presented as
median values
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Advanz 3 StudyCD4<100/uL; n=89
TDF+FTC+ EFV or ATZ/r or LPV/r
Mirò et al. JAIDS, 2015
Immuno StudyCD4<50>250/uL, n=35
TDF+FTC+ EFV or DRV 800mg/r
Tincati et al. under review Data are presented as
median values
See also: McComsey, AIDS, 2012
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Similar reduction of T-cell activation by different cART class318 HIV+ starting first cART (170 PI; 128 NNRTI; 20 INI)
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What drives persistent immune activation/inflammation in cART-treated disease?
• Gut epithelial barrier dysfunction, microbiome and microbial translocation
• Co-infections (CMV et al….)• Residual HIV replication• Thymic dysfunction and residual defects in adaptive
immune responses• Lack of immunoregulatory responses- Lymphoid fibrosis• Co-morbid conditions (metabolic syndrome, central
adiposity)
![Page 79: What drives persistent immune activation/inflammation in cART-treated HIV-1? Giulia Marchetti, MD, PhD Dept of Health Sciences, Clinic of Infectious Diseases](https://reader030.vdocuments.mx/reader030/viewer/2022013004/56649f305503460f94c4b73f/html5/thumbnails/79.jpg)
Isgro’ et al. CID 2008
Bellistrì et al. PlosOne 2010
Bone marrow alterations upon cART
23 HIV+ cART-treated
cARTcART
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Douek et al. Nature 1998
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What drives persistent immune activation/inflammation in cART-treated disease?
• Gut epithelial barrier dysfunction, microbiome and microbial translocation
• Co-infections (CMV et al….)• Residual HIV replication• Thymic dysfunction and residual defects in adaptive
immune responses• Lack of immunoregulatory responses- Lymphoid fibrosis• Co-morbid conditions (metabolic syndrome, central
adiposity)
![Page 82: What drives persistent immune activation/inflammation in cART-treated HIV-1? Giulia Marchetti, MD, PhD Dept of Health Sciences, Clinic of Infectious Diseases](https://reader030.vdocuments.mx/reader030/viewer/2022013004/56649f305503460f94c4b73f/html5/thumbnails/82.jpg)
In untreated HIV: hyper-inflamed
cytokine milieu → Treg response → TGF-β → collagen deposition → Fibrosis → Reduced IL-
7 → Reduced T cell regeneration →
inflammation
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Zeng et al. PlosPathogens 2012
Recovery of collagen deposition according to the stage of cART start
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Schaker et al. JID 2002
Collagen deposition in lymphoid tissues before cART substantially impacts the dynamics of T-lymphocyte reconstitution
Zeng et al. PlosPathogens 2012
LN
Asmuth et al. AIDS 2015
GUT
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Tissue fibrosis as driver of immune activation?
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Increased CD90+TLR4+ activated myofibroblast in HIV+ duodenal mucosa (a-SMA+FAP+)
Asmuth et al. AIDS 2015
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Pinchuck IV et al. Curr Gatroenterol Rep 2010
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LPS stimulation of cultured intestinal myofibroblast from HIV+ patients upregulates pro-fibrotic mediators
Asmuth et al. AIDS 2015
+ LPS
+ LPS
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Klatt et al. Immunol Rev 2013
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Thanks *Dept of Health Sciences- Clinic of Infectious Diseases- Univ of Milan, San Paolo H
Esther MerliniCamilla TincatiElvira S CannizzoGiuseppe AnconaGiusi M BellistrìFrancesca BaiMatteo BasilissiAntonella d’Arminio Monforte***all the patients and staff
*Dept of Health Sciences- Pathology Dept- Univ of Milan, S Paolo Ho
Delfina Tosi, Solange Romagnoli (now Roche Diagnostics, Germany)
Alessandro Cozzi-Lepri, Miriam Lichtner, Antonella d’Arminio Monforte
*Clinic of Infect DisUniv of Milan, L Sacco HStefano Rusconi, Massimo Galli